Hyperpolarized C-13 Spectroscopic Imaging Informs on Hypoxia-Inducible Factor-1 and Myc Activity Downstream of Platelet-Derived Growth Factor Receptor

Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California 94158, USA.
Cancer Research (Impact Factor: 9.33). 10/2010; 70(19):7400-10. DOI: 10.1158/0008-5472.CAN-10-0883
Source: PubMed

ABSTRACT The recent development of hyperpolarized (13)C magnetic resonance spectroscopic imaging provides a novel method for in vivo metabolic imaging with potential applications for detection of cancer and response to treatment. Chemotherapy-induced apoptosis was shown to decrease the flux of hyperpolarized (13)C label from pyruvate to lactate due to depletion of NADH, the coenzyme of lactate dehydrogenase. In contrast, we show here that in PC-3MM2 tumors, inhibition of platelet-derived growth factor receptor with imatinib reduces the conversion of hyperpolarized pyruvate to lactate by lowering the expression of lactate dehydrogenase itself. This was accompanied by reduced expression of vascular endothelial growth factor and glutaminase, and is likely mediated by reduced expression of their transcriptional factors hypoxia-inducible factor-1 and c-Myc. Our results indicate that hyperpolarized (13)C MRSI could potentially detect the molecular effect of various cell signaling inhibitors, thus providing a radiation-free method to predict tumor response.

Download full-text


Available from: Christopher S Ward, Sep 28, 2015
34 Reads
  • Source
    • "Using this technique, non-invasive tumor detection has been achieved in vivo as a result of the altered pH in tumor tissue [3] or the altered pyruvate metabolism in tumor cells [4]. This technique also enables spectroscopic evaluation of the tumor response to anti-tumor therapies [5], [6], [7]. Interestingly, it has been also reported that the hyperpolarized 13C glutamate generated by the DNP technique can be a metabolic biomarker of the mutational status of isocitrate dehydrogenase 1 gene in glioma in vivo by detecting the activity of the branched-chain amino acid transaminase 1 [8]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Morphological imaging precedes lesion-specific visualization in magnetic resonance imaging (MRI) because of the superior ability of this technique to depict tissue morphology with excellent spatial and temporal resolutions. To achieve lesion-specific visualization of tumors by MRI, we investigated the availability of a novel polymer-based tracer. Although the 13C nucleus is a candidate for a detection nucleus because of its low background signal in the body, the low magnetic resonance sensitivity of the nucleus needs to be resolved before developing a 13C-based tracer. In order to overcome this problem, we enriched polyethylene glycol (PEG), a biocompatible polymer, with 13C atoms. 13C-PEG40,000 (13C-PEG with an average molecular weight of 40 kDa) emitted a single 13C signal with a high signal-to-noise ratio due to its ability to maintain signal sharpness, as was confirmed by in vivo investigation, and displayed a chemical shift sufficiently distinct from that of endogenous fat. 13C-PEG40,000 intravenously injected into mice showed long retention in circulation, leading to its effective accumulation in tumors reflecting the well-known phenomenon that macromolecules accumulate in tumors because of leaky tumor capillaries. These properties of 13C-PEG40,000 allowed visualization of tumors in mice by 13C spectroscopic imaging. These findings suggest that a technique based on 13C-PEG is a promising strategy for tumor detection.
    PLoS ONE 07/2014; 9(7):e102132. DOI:10.1371/journal.pone.0102132 · 3.23 Impact Factor
  • Source
    • "In the last few years, changes in the hyperpolarized [1-13C]lactate signals observed in vivo following injection of [1-13C]pyruvate pre-polarized via dynamic nuclear polarization (DNP) were shown to be a marker for tumor progression or early treatment response [6]–[12]. This method takes advantage of the up-regulation of glycolysis that is well known in many tumor types [13]–[15], and the recent development of the DNP-dissolution method [16], [17] that allows real time observation of cellular enzymatic reactions in vivo with hyperpolarized 13C substrates. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Following radiation therapy (RT), tumor morphology may remain unchanged for days and sometimes weeks, rendering anatomical imaging methods inadequate for early detection of therapeutic response. Changes in the hyperpolarized [1-(13)C]lactate signals observed in vivo following injection of pre-polarized [1-(13)C]pyruvate has recently been shown to be a marker for tumor progression or early treatment response. In this study, the feasibility of using (13)C metabolic imaging with [1-(13)C]pyruvate to detect early radiation treatment response in a breast cancer xenograft model was demonstrated in vivo and in vitro. Significant decreases in hyperpolarized [1-(13)C]lactate relative to [1-(13)C]pyruvate were observed in MDA-MB-231 tumors 96 hrs following a single dose of ionizing radiation. Histopathologic data from the treated tumors showed higher cellular apoptosis and senescence; and changes in the expression of membrane monocarboxylate transporters and lactate dehydrogenase B were also observed. Hyperpolarized (13)C metabolic imaging may be a promising new tool to develop novel and adaptive therapeutic regimens for patients undergoing RT.
    PLoS ONE 06/2013; 8(2):e56551. DOI:10.1371/journal.pone.0056551 · 3.23 Impact Factor
  • Source
    • "Conversely, several reports have been published reporting normalization of glucose metabolism as an indication of response to targeted treatment [8], [9]. A decrease in pyruvate to lactate conversion in response to treatment with phosphoinositide 3-kinase (PI3K) or receptor tyrosine kinase (RTK) inhibitors was shown in different tumor types by 13C MRS [10], [11]. Phosphocholine (PC) or, clinically, total choline (tCho, comprised of choline, PC and glycerophosphocholine) was also identified in several MR studies as an important biomarker that is generally elevated in cancer cells and associated with more aggressive and invasive phenotypes [12]–[20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Targeted therapeutic approaches are increasingly being implemented in the clinic, but early detection of response frequently presents a challenge as many new therapies lead to inhibition of tumor growth rather than tumor shrinkage. Development of novel non-invasive methods to monitor response to treatment is therefore needed. Magnetic resonance spectroscopy (MRS) and magnetic resonance spectroscopic imaging are non-invasive imaging methods that can be employed to monitor metabolism, and previous studies indicate that these methods can be useful for monitoring the metabolic consequences of treatment that are associated with early drug target modulation. However, single-metabolite biomarkers are often not specific to a particular therapy. Here we used an unbiased 1H MRS-based metabolomics approach to investigate the overall metabolic consequences of treatment with the phosphoinositide 3-kinase inhibitor LY294002 and the heat shock protein 90 inhibitor 17AAG in prostate and breast cancer cell lines. LY294002 treatment resulted in decreased intracellular lactate, alanine fumarate, phosphocholine and glutathione. Following 17AAG treatment, decreased intracellular lactate, alanine, fumarate and glutamine were also observed but phosphocholine accumulated in every case. Furthermore, citrate, which is typically observed in normal prostate tissue but not in tumors, increased following 17AAG treatment in prostate cells. This approach is likely to provide further information about the complex interactions between signaling and metabolic pathways. It also highlights the potential of MRS-based metabolomics to identify metabolic signatures that can specifically inform on molecular drug action.
    PLoS ONE 10/2011; 6(10):e26155. DOI:10.1371/journal.pone.0026155 · 3.23 Impact Factor
Show more